Many patients with acute and chronic pain do not receive adequate pain relief despite the wide variety of analgesic medications that are currently available, either because the medications are not effective in all patients, or because their use is limited by toxicity or intolerability. The limitations of currently available analgesic therapies include adverse central nervous system effects, nausea and vomiting, constipation, gastrointestinal bleeding and ulceration, cardiovascular events, renal toxicity, and potential for abuse. Inadequate pain relief has a profound impact on the quality of life for millions of people worldwide with an associated substantial cost to society, including healthcare cost and loss of productivity.
Neurotrophins are a family of peptide growth factors that play a role in the development, differentiation, survival and death of neuronal and non-neuronal cells (Chao, M. et. al., (2006), ClinSci (Lond); 110:167). Nerve growth factor (NGF) was the first neurotrophin to be identified, and its role in the development and survival of both peripheral and central neurons during the development of the nervous system is well characterized (Smeyne, R. J., et. al., (1994), Nature 368:166-169; Crowley, C. et. al., (1994), 76:1001-1011). In the adult, NGF is not required as a survival factor but acts as a pain mediator that sensitizes neurons (Pezet, S. et. al., (2006), Ann Rev Neurosci 29:507-518). Nerve growth factor activity is mediated through 2 different membrane-bound receptors, the high-affinity tyrosine kinase type 1 (TrkA) and the low-affinity p75 neurotrophin receptors.
Administration of NGF has been shown to provoke pain in both rodents (Lewin, G. R., et. al., (1994), Eur. J. Neurosci 6:1903-1912) and humans (McArthur, J. C., et. al., (2000), Neurology 54:1080-1088), while NGF antagonists have been shown to prevent hyperalgesia and allodynia in animal models of neuropathic and chronic inflammatory pain (Ramer, M. S. et. al., Eur J Neurosci 11:837-846). Humans with mutations in TrkA (hereditary sensory and autonomic neuropathy IV) or NGF (hereditary sensory and autonomic neuropathy V) have been identified with a loss of deep pain perception (Indo, Y. et. al., (1996), Nature Genetics, 13:485-488), Einarsdottir, E., et. al., (2004), Human Molecular Genetics 13:799-805). In addition, NGF is known to be elevated in the synovial fluid of patients with rheumatoid arthritis and other types of arthritis (Aloe, L. et. al., (1992), Arthritis Rheum 35:351-355; Halliday, D. A., (1998), Neurochem Res. 23:919-922), and to be up-regulated in injured and inflamed tissues in conditions such as cystitis, prostatitis, and chronic headache (Lowe, E. M., et. al., (1997), Br. J. Urol. 79:572-577; Miller, L. J., et. al., (2002), Urology 59:603-608; Sarchielli, P. et. al., (2001), Neurology 57:132-134).
There is an unmet need for agents that alleviate pain in individuals who have a history of inadequate pain relief, or who are intolerant to standard analgesic therapy. Fasinumab is a fully-human high-affinity monoclonal antibody directed against NGF. By selectively blocking NGF, fasinumab has the potential to be effective in modulating NGF-associated pain without some of the adverse side effects of other analgesic medications, such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs).